Our understanding of stem cell biology, especially in regards to its use for therapeutic cardiovascular regeneration, has continued at a staggering pace. Over the past few years, the identification of endogenous cardiac stem cells has raised the exciting possibility of harnessing these cells for cardiac repair. Recently, our laboratory has observed the existence of a cardiac progenitor cell population. These so termed cardiac side-population (CSP) cells, identified in adult hearts by their distinct Hoechst dye efflux pattern, represent a distinct cardiac progenitor cell population, capable of both biochemical and, more importantly, functional cardiomyogenic differentiation through a process mediated by coupling with adult cardiomyocytes. Moreover, after myocardial infarction (Ml), CSP cells are acutely depleted, and are restored through self-renewal of endogenous CSP cells and homing of extra-cardiac bone marrow-derived side population (BMSP) stem cells. Following homing to the injured hearts, BMSP adopt an immunophenotype similar to endogenous CSP cells. As such, utilizing a multidisciplinary approach of in-vitro and in-vivo methodologies, the main goal of this proposal is to delineate the signaling pathways regulating the proliferation and differentiation of CSP cells. Additionally, we will determine the functional significance of BMSP cell homing to injured myocardium, with the ultimate goal of harnessing these adult stem cells for physiologically significant cardiac regeneration.